The purpose of this application is to determine whether a peripherally acting mu-opioid receptor antagonist, methylnaltrexone (MTNX), attenuates certain subjective effects of a mu opioid analgesic, morphine, and to determine if MTNX changes the abuse liability-related profile of morphine to be more positive in healthy volunteers. It is currently used in patients on chronic opioid therapy for the relief of opioid-induced constipation, a peripherally-mediated side effect. Because it does not cross the blood-brain barrier, it does not antagonize the analgesic effect of opioids that is centrally mediated. Results from two small-N studies conducted in healthy volunteers indicate that aversive subjective effects that are induced by opioids, such as nausea, might be attenuated by pretreatment with MTNX. The study results were not definitive for several reasons, and we feel a more systematic laboratory analysis would clearly be of value. We intend to use MTNX as a probe to determine whether, and to what extent, certain subjective effects of opioids are mediated by peripheral opiate receptors. Healthy volunteers with no history of opioid abuse or dependence will participate in a placebo- controlled, double-blind, randomized, crossover trial in which they will be exposed to placebo, morphine alone (0.14 mg/kg, iv), two doses of MTNX (0.225, 0.45 mg/kg, sc) combined with morphine, and the higher dose of MTNX tested alone. The primary dependent measure in this study is subjective effects. Secondary measures include physiological and psychomotor effects. The study is significant from a basic psychopharmacology and pharmacology standpoint in that it will address the extent to which prototypic subjective effects of mu opioids are mediated at peripheral opiate receptors. It is significant from a clinical standpoint in that will address whether MTNX might have potential therapeutic implications beyond its ability to relieve constipation. It is significant and innovative from an abuse liability standpoint. Abuse liability of a drug is putatively influenced not only by positive effects of a drug but also negative effects, so if negative effects of morphine are attenuated by MTNX, the abuse liability-related profile of morphine may shift to where morphine is predominantly liked by the majority of healthy volunteers, a finding which would run counter to a number of studies in the extant literature with healthy volunteers. PUBLIC HEALTH RELEVANCE: The purpose of this application is to determine if blockade of peripheral opiate receptors alters subjective effects of opioids, some of which are considered aversive. This could be beneficial to patients in pain, some of whom forgo taking opioid analgesics because of their side effects.